11-27368470-C-G

Variant names:

• chr11-27368470-C-G
• NM_018490.5:c.2253G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018490.5(LGR4):​c.2253G>C​(p.Trp751Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LGR4 NM_018490.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.87
• Publications: 0 publications found

Genes affected

LGR4 (HGNC:13299): (leucine rich repeat containing G protein-coupled receptor 4) The protein encoded by this gene is a G-protein coupled receptor that binds R-spondins and activates the Wnt signaling pathway. This Wnt signaling pathway activation is necessary for proper development of many organs of the body. [provided by RefSeq, Oct 2016]

LGR4 Gene-Disease associations (from GenCC):

• delayed puberty, self-limited

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018490.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGR4	NM_018490.5	MANE Select	c.2253G>C	p.Trp751Cys	missense	Exon 18 of 18	NP_060960.2	Q9BXB1-1
	LGR4	NM_001346432.2		c.2181G>C	p.Trp727Cys	missense	Exon 17 of 17	NP_001333361.1	Q9BXB1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGR4	ENST00000379214.9	TSL:1 MANE Select	c.2253G>C	p.Trp751Cys	missense	Exon 18 of 18	ENSP00000368516.4	Q9BXB1-1
	LGR4	ENST00000389858.4	TSL:1	c.2181G>C	p.Trp727Cys	missense	Exon 17 of 17	ENSP00000374508.4	Q9BXB1-2
	LGR4	ENST00000937760.1		c.2184G>C	p.Trp728Cys	missense	Exon 17 of 17	ENSP00000607819.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.023	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.59		Gain of catalytic residue at L752 (P = 0.0096)
MVP		0.82
MPC		1.1
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.79
gMVP		0.95
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr11-27390017;